The present invention relates to nanoparticles comprising a poorly water-soluble drug, a poorly aqueous soluble non-ionizable cellulosic polymer having an ether- or ester-linked alkyl substituent, and a poorly aqueous soluble polymeric amphiphilic non-ionizable block copolymer having a hydrophobic block that is a polylactone and a hydrophilic block that is polyethylene oxide or polyethylene glycol.
It is known that poorly water-soluble drugs may be formulated as nanoparticles. Nanoparticles are of interest for a variety of reasons, such as to improve the bioavailability of poorly water-soluble drugs, to provide targeted drug delivery to specific areas of the body, to reduce side effects, or to reduce pharmacokinetic variability in vivo.
A variety of approaches have been taken to formulate drugs as nanoparticles. One approach is to decrease the size of crystalline drug by grinding or milling the drug in the presence of a surface modifier. See, e.g., U.S. Pat. No. 5,145,684. Another approach to forming nanoparticles is to precipitate the drug in the presence of a film forming material such as a polymer. See, e.g., U.S. Pat. No. 5,118,528.
Nanoparticles containing a drug and a non-ionizable polymer are known in the art. Bodmeier and Chen (J. Controlled Release, 12, (1990) 223-233) describe nanoparticles prepared from ethylcellulose and a variety of aqueous soluble surfactants, as well as mixtures of ethylcellulose and poly(methyl methacrylate). U.S. Pat. No. 5,919,408 discloses nanoparticles prepared from ethylcellulose and the aqueous soluble surfactants sodium dodecyl sulphate and a polyoxyethylene-polyoxypropylene copolymer. U.S. Pat. No. 5,118,528 discloses nanoparticles prepared from poly(lactic acid) and a polyoxyethylene-polyoxypropylene copolymer. U.S. Pat. No. 5,543,158 discloses nanoparticles prepared from blends of poly(lactide-co-glycolide) and poly(lactide-co-glycolide-b-ethylene glycol). EP 1 180 062 B1 discloses nanoparticles prepared from blends of poly(lactic acid) and a polyoxyethylene-polyoxypropylene copolymer.
While these methods of forming nanoparticles are functional, nevertheless there remain a number of problems associated with the use of nanoparticles to deliver pharmaceutical compounds to the body. First, it is difficult to form very small particles. Second, once particles of the target size are formed, they must remain stable over time in a variety of different environments. Often, the nanoparticles are formed in a liquid environment. The nanoparticles must be stabilized so that they do not aggregate in solution into larger particles. In addition, the drug in the nanoparticles must be stabilized so that it does not crystallize in the use environment.
Third, the nanoparticles must be well tolerated in the body. Often surface modifiers such as surfactants are used to stabilize the nanoparticles, but such materials can have adverse physiological effects when administered in vivo. In addition, such materials are often labile, dissolving into the aqueous use environment, resulting in undesirable agglomeration of nanoparticles. Ionizable stabilizers are often not ionized in the low pH of a gastric environment, resulting in agglomeration of the nanoparticles in the stomach. Additionally, without a surface modifier present, the surface of the nanoparticles is unprotected, leading to a decrease in performance and stability.
Finally, the nanoparticles must be formulated to provide optimum delivery. The nanoparticles should provide good bioavailability of the poorly water-soluble drug. In some applications, it is desired that the nanoparticles provide reduced differences in exposure when administered orally to subjects in the fed state versus in the fasted state. Alternatively, it may be desired to provide controlled or sustained release of the drug below pre-determined dissolved drug concentrations in vivo. It may be desired to administer the nanoparticles through non-oral routes, such as by parenteral, topical, or ocular delivery.
Accordingly, there is still a continuing need for nanoparticles that are stable, in the sense of not forming crystalline drug over time or aggregating into larger particles, and that improve the bioavailability of low-solubility drugs.